The present invention relates to an anesthetic composition for intravenous injection comprising 2,6-diisopropylphenol (hereinafter, referred to as xe2x80x9cpropofolxe2x80x9d). More specifically, the present invention relates to an anesthetic composition for intravenous injection, characterized in that it contains propofol and a poloxamer as the surfactant.
Propofol is highly lipid-soluble and has a characteristic property that it can readily permeate biomembranes such as blood brain barrier (BBB). Therefore, it has been used as a useful anesthetic agent.
In general, anesthetic agents are eliminated through their metabolism and excretion in living body. When an anesthetic agent having a long half-life is repeatedly administered in a large amount, it may be greatly accumulated into storage tissues such as skeletal muscles, adipose tissues, etc., so that the recovery may be delayed. Thus, if such anesthetic agent is administered for a long period, since it may be diffused from storage tissues into the blood to increase its plasma concentration, the recovery rate of patients may be delayed and the psychomotor function may also be damaged over long period.
Contrary to this, an alkylphenol derivative, propofol, has a short half-life and thus, has some clinical characteristic features that it can be rapidly migrated into the brain to show a rapid onset of anesthetic effect and further, rapidly re-distributed into other tissues and then metabolized so that the patients can be rapidly recovered from the anesthetic state. In addition, propofol may cause less side effects such as headache, nausea, vomiting, etc., than other anesthetic agents in patients and its accumulation into human body can be minimized in spite of its administration for a long period. Therefore, it has been known that propofol is the most ideal anesthetic agent for intravenous injection.
Further, while many anesthetic agents commonly used in the clinical field are in a gaseous state, propofol is useful for intravenous injection and therefore, can be very effectively used as a local analgesic adjuvant due to its hypnotic and sedative activities, an anesthetic agent for patients for whom pulmonary respiration should be cared, an anesthetic agent used under conscious state, etc., or for patients under medical treatment in intensive care unit (ICU) or patients in serious state, etc.
In spite of such clinical advantages of propofol, the development of its injectable formulations is very difficult since propofol exists in the non-ionized state (pKa=10.4) in blood and has physico-chemical properties including a unique high lipid solubility (octanol water partition coefficient 4.33).
Thus, since water may substantially be an essential solvent in preparing all pharmaceutical formulations including anesthetic agents, it is very difficult to formulate lipid-soluble drugs such as propofol into pharmaceutical preparations using water as the solvent. In order to solve such problem, lipid-soluble drugs which are generally poorly soluble in water have been developed into such forms as emulsions, microemulsions, micelles, etc., using a surfactant. However, it also possesses a limitation.
In the prior art, Zeneca Inc. has prepared and sold the formulation wherein 1% propofol is dissolved in 16% CREMAPHOR EL (Polyoxyl 35 castor oil) as a non-ionic surfactant. However, this formulation causes some side effects such as anaphylactoid reaction as an allergic reaction in some patients, which is believed to be caused by CREMAPHOR EL (Polyoxyl 35 castor oil) contained therein in an excessive amount. Therefore, in order to overcome such side effects caused by the surfactant Zeneca Inc. has developed the injectable formulation (trade name: Diprivan) in the form of a novel fat emulsion, wherein 1% propofol is dissolved in 10% soybean oil and then stabilized with 1.25% egg phosphatide.
However, it has been indicated that the emulsions for intravenous injection containing lipid materials have many side effects and problems, which can be generally and roughly summarized as the following five issues:
First, the emulsion is thermodynamically unstable and therefore, is fused in the course of time to make the formulation unstable.
Second, there is a possibility of causing embolism due to particles in size of 1 xcexcm or more which may possibly be present in heterogeneous emulsions.
Third, the active ingredient and lipid components may cause a pain when the formulation is injected.
Fourth, since the lipid component may serve as a cause of the acceleration of microorganism growth in the absence of any preservative, strict aseptic techniques must be maintained when handling these formulation.
Finally, the administration of lipid components as the main ingredient may result in hyperlipidemia.
Thus, in the field of anesthesiology, the development of novel formulation which can solve the above-mentioned problems has been on the rise as the forefront subject. In thxe2x96xa1xc3x85is regard, Zeneca Inc. has developed the formulation comprising a novel composition having an antiseptic activity by addition of a preservative (EDTA) in order to inhibit the microorganism growth due to lipid components amongst the above-mentioned problems (U.S. Pat. No. 5,714,520). However, this formulation still has the unsolved problems including physical unstability, pain at injection site, embolism, hyperlipidemia, Further, in order to improve such problems, the formulations have recently been studied using inclusion complexation of propofol with biodegradable surfactants or cyclodextrin (Giuseppe Trapani et al., J. Pharm. Sci., 1998, 87, 514-518), the concept of prodrugs (Sagara Y., J. Neurochem., 1999, 73, 2524-2530), etc. In addition, the study to reduce the pain during injection by administration in combination with such neuroblocking agents as lidocain has been actively and extensively practiced from all parts of the world (Parmar A. K., Anaesthesia, 1998, 53, 79-83). However, such study has not been verified for their effect as yet and thus, not been actually completed. Therefore, the need an anesthetic composition for intravenous injection, which is capable of providing the efficient formulation and minimized side effects, has been very gradually increased.
Thus, the technical subject of the present invention is to provide a useful anesthetic composition for intravenous injection which can be efficiently converted into the desired formulation and further, can minimize the side effects, with overcoming the above-mentioned problems involved in the prior art.
The technical subject of the present invention is to provide a useful anesthetic composition for intravenous injection which can be efficiently converted into the desired formulation and further, can minimize the side effects, with overcoming the above-mentioned problems involved in the prior art.
In order to achieve said technical subject, the present invention provides an anesthetic composition for intravenous injection, which comprises propofol and a poloxamer as the surfactant.
According to the present invention, it is preferred that propofol is contained in an amount of 1 to 2% by weight of the total composition.
Further, the composition of the present invention may additionally contain at least one co-surfactant selected from the group consisting of SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), egg lecithin, LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol, in addition to a Poloxamer POLOXAMER (Polyoxyethylene-polyoxypropylene copolymer) as the surfactant.
In the present invention, it is particularly preferred to use POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer) as the POLOXAMER (Polyoxyethylene-polyoxypropylene copolymer). It is desirable to have POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer) in an amount of 0.1 to 5% by weight of the total composition.
In addition, the composition of the present invention is preferably present in the form of an oil-in-water microemulsion having a particle size of 100 nm and below.
In the composition of the present invention, it is preferred that the content of propofol amounts to 1 to 2% by weight of the total composition and the content of POLOXAMER (Polyoxyethylene-polyoxypropylene copolymer) amounts to 0.1 to 10% by weight of the total composition. The POLOXAMER (Polyoxyethylene-polyoxypropylene copolymer) which can be preferably used in the present invention include POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer) and POLOXAMER 188 (Polyoxyethylene-polyoxypropylene copolymer), with POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer) being particularly preferable in providing the effect of the present invention. In case of POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer), it is preferably contained in an amount of 0.1 to 5%, by weight of the total composition.
Further, the composition of the present invention can additionally contain an agent for pH adjustment and an agent for isotonicity. The agent for pH adjustment is preferably sodium hydroxide and the agent for isotonicity is particularly preferable to use glycerol.
Hereinafter, the present invention will be more specifically explained.
The composition of the present invention is characterized in that it contains propofol and a poloxamer as the surfactant.
The poloxamers are a block copolymer composed of hydrophilic polyoxyethylene and hydrophobic polyoxypropylene, which allows that in the aqueous solution the lipid-soluble portion formed from polyoxypropylene can include the drug therein and the hydrophilic polyoxyethylene portion is placed on the outside of the core so that it can be hydrated with water. All of poloxamers have a substantially similar composition to each other and are classified into many varieties depending on the ratio of polyoxyethylene/polyoxypropylene content. The poloxamers are a very stable material to exist in a stable state in an aqueous solution containing acids, alkalis and even the metals. In addition, they have been known as being a non-toxic and non-irritant material which is not metabolized in a living body. Poloxamers are described in USP XXIII and have been once used as a stable excipient by U.S. Food and Drug Administration (FDA). Further, they have been known as having less side effects than others when they are intravenously injected.
The present invention provides an anesthetic composition for intravenous injection which contains propofol and poloxamer alone or in combination with other co-surfactant.
In the composition of the present invention, it is preferred that the content of propofol amounts to 1 to 2% by weight of the total composition and the content of poloxamer amounts to 0.1 to 10% by weight of the total composition. The poloxamer which can be preferably used in the present invention include poloxamer 407 and poloxamer 188, with poloxamer 407 being particularly preferable in providing the effect of the present invention. In case of poloxamer 407, it is preferably contained in an amount of 0.1 to 5% by weight of the total composition.
Since poloxamers used in the present invention can allow the microemulsification of the composition even by using a smaller amount than prior surfactants., the toxicity of anesthetic composition containing propofol as the active ingredient can be significantly reduced.
The composition of the present invention can additionally contain at least one co-surfactant selected from the group consisting of SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), egg lecithin, LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol, with SOLUTOL HS 15 (Macrogol-15 Hydroxystearate) and egg lecithin being particularly preferable. When SOLUTOL HS 15 (Macrogol-15 Hydroxystearate) is added in an amount of 0.1 to 10% by weight of the total composition or egg lecithin is added in an amount of 0.1 to 5% by weight of the total composition, they can show the most excellent effect.
According to the preferable embodiment of the present invention, the composition of the present invention is in the form of an oil-in-water microemulsion having a particle size of 100 nm and below.
The microemulsions have the particle size of 100 nm and below, are thermodynamically stable and do not cause any phase separation in the course of time. The micromeulsions are classified into an oil-in-water and a water-in-oil forms, wherein the former is preferable in the present invention. The oil-in-water microemulsion means ultrafine elementary particles protected in the water phase, which is formed by dissolving the drug in the oil phase and then enclosing the drug in the surfactant and/or co-surfactant when the drug is hydrophobic. They have physico-chemical properties that they are thermodynamically stable, allow to disperse the immiscible two liquid phases into a single phase can be prepared spontaneously without putting external energy into the procedures for their preparation, and are apparently transparent since the incident light is totally reflected on the surface of particles due to the low concentration and small size of the enclosed particles as finally prepared, and the like.
The thermodynamic stability of microemulsions can be ensured by selecting a suitable surfactant to reduce the surface tension and further by adding the co-surfactant to increase the fluidity of particle membrane.
In the present invention, poloxamers used as the surfactant have a high hydrophilic/lipophilic balance and therefore, can allow that the composition can be readily prepared in the form of an oil-in-water microemulsion.
First of all, the microemulsion thus prepared can overcome the problem of emulsions due to a instability of the formulation""since it has characteristic features that it is thermodynamically stable in comparison to the known emulsions, can be readily prepared spontaneously at room temperature and is a transparent solution. In addition, it has advantages in that it forms small and uniform particles in size of 100 nm and below so that it can be readily filtered through the filter in size of 0.22 xcexcm to make a sterile filtration possible and to reduce the risk of embolism to be caused by some large particles and lipid. Further, the hydrophilicity of the stably enclosed drug can sufficiently contribute for reducing the pain when it is injected, since when it is injected via intravenous route, it is dispersed by rapid blood flow to reduce the direct contact with the membrane of blood vessel. Moreover, since it does not contain any lipid component which is used in lipid emulsions, it also reduce the risk of hyperlipidemia which may be raised due to lipid components.
The composition of the present invention can be prepared by further adding an agent for pH adjustment. Although any agent for pH adjustment conventionally used in this may can be used without any special limitation, sodium hydroxide (NaOH) is particularly preferably used. In addition, the composition of the present invention can also contain an agent for isotonicity, if appropriate. Similarly, although any agent for isotonicity conventionally used in this art can be irrespectively used, it is preferable to select glycerol.
The composition of the present invention is typically a sterile, aqueous preparation and has a very small particle size (100 nm and below). Therefore, it can be formulated into an injectable solution in a sterile state by a simple filtration, rather than the final sterilization using autoclave. It is preferred to practice all the procedures for preparation under nitrogen.